Alkylene-bis-(n-methyl-2, 6-dialkylanilines)



2,921,093 ALKYLENE-BIS-(N-METHYL2,6-DIALKYL- ANILINES) Hastings on Hudson, and Louis assignors to US. Vitamin a corporation of Dela- Seymour L. Shapiro,

Freedman, Bronxville, N.Y., & Pharmaceutical Corporation,

ware

No Drawing. Application January Serial No. 709,475

This invention relates to alkylene-bis-(N-methyl-2,6- dialkylanilines) having the following formula:

wherein R is methyl and straight chain lower alkyl, and Y is a bivalent straight chain hydrocarbon'linking element whichrnay be saturated or unsaturated, and which .containsat least two, and not more than twelve carbon 'atoms and preferably two to six carbon atoms. I

The compounds of this invention thus belong to the class of bisanilines whereineach anilino nitrogen bears one methyl group, and the two anilino nitrogens, are joined by the hydrocarbon linking element "1Q "lri turn, each of the. two ,phenyl groups inthe formula has an alkyl group in both the 2 and 6 pyzasitioris,- the position hearing the nitrogen being designated as the lposition. 'A consequence of this disposition ofth'e groups is that due to steric hindrance there "is inhibitionfof .typi cal aniline resonance, as well as steric inhibition of 'sol'vation "or the structures concerned. The compounds of this invention are accordingly distinct from such substances wherein the anilino nitrogens do not bear methyl groups, and wherein the phenyl rings do not have substituents in the 2,6 positions. The compounds of this invention can be neutralized by hydrochloric acid, hydrobromic acid and the like, and in this form show desirable pharmacological properties, particularly as central nervous system depressants.

The compounds of this invention are prepared by a variety of procedures which are described below as methods A and B.

Method A.-The 2,6-dialkylaniline is first converted to the N-methyl-2,6-dialkylaniline by treatment with methyl iodide. An excess of the N-methyl-2,6-dialkylaniline is reacted with XY-X, this generic formula being a compound of the type wherein Y has the same significance as described above, and X is selected from the groups consisting of halogen, and p-toluene sulfate, and the desired alkylene-bis-(N-methyl-2,6-dialkylaniline) isolated.

Method B.-An excess of 2,6-dialkylaniline is reacted with X--Y-X and the formed alkylene-bis-(2,6-dialkylaniline) is isolated and converted by treatment with formaldehyde-formic acid to the desired alkylene-bis-(N- methyl-2,6-dialkylaniline) As more specifically illustrative of the preparation of the compounds contemplated by this invention, the 01- Taiented Jan. 12, 1960 lowing specific examples of the preparation of specific by this invention will serve to by the various methods used.

compounds contemplated exemplify the preparation 7 E AMP E I N-methyl-2,6-dir ethylaniline A mixture of 140 g.- (1.14 moles) of 2,6-dimethyl aniline and 140 g. (0.98 mole) of methyl iodideJwas heated on the-steambath for 0.25 hour. The crystalline mass which formed, 217 g., .was separated. and rinsed with ether, dried and treated with 300 ml. .of water. After addition of excess 6 N sodium hydroxide,.the prod uct was extracted with three'200' ml. portions of ether. Thecombined ether extracts were dried (magnesium 'sulfate), filtered, theether" removed, andthe residue. distilled. The product, 96.7 g. (69%), was collected, boiling at 206 C. U 7' EXAM E II N -methyl-2,6-diethylqriiline In a manner' similar to that described above using 2 ,6-

diethylaniline, the product was obtained in 81% yield boiling at 229-231 C.

Analysis.-Calcd. for C HwN: C,80.9; H, 10.5; N, 8.6. Found: C, 80.8; H, 10.7; N, 8.6.

' EXAMPLE III" Method A.Ethylene-bis-(N-methyl 2,6 dim ethylqniline) A mixture of- 27. g. (0.2 mole) of N-methyl-2,6-dimethylaniline, 9.4 g. (0.05 mole) of ethylene dibromide and 50 mg. of potassium iodide was heated in an oil bath at 140 C. for 1 hour. After addition of ml. of water and 100 ml. of 6 N sodium hydroxide, the product was extracted with three 100 ml. portions of ether. The combined ether extract was dried (magnesium sulfate), filtered, the ether removed and the residue distilled. The product, 2.25 g. (15%) boiled at 148-152 C./0.2 mm.

Analysis.-Calcd for C H N C, 81.0; H, 9.5; N, 9.4. Found: C, 81.1; H, 9.5; N, 9.2.

EXAMPLE IV Method B. Trimethylene-bis-(N-methyl-2,6-dimethylaniline To a solution of 12.4 g. (0.044 mole) of trimethylenebis-(2,6-dimethylaniline) in 25 ml. (0.56 mole) of 87% formic acid, there was added 14 ml. (0.17 mole) of 37% aqueous formaldehyde and the mixture heated on a steam bath for ten hours. After addition of 60 ml. of N hydrochloric acid, the reaction mixture was concentrated in vacuo, the residue dissolved in 100 ml. of water and treated with 40 ml. of 6 N sodium hydroxide. The product was extracted with three 100 m1. portions of ether, the com.- bined ether extracts dried (magnesium sulfate), filtered, the ether removed and the residue distilled. The product obtained, 5.9 g. (43%), boiled at 158-163 C,/0,.05

Typifying, but not limiting the products herein, there is reported in Table I, a series of compounds with their physical properties and the method used for their prey aration.

a A '4'" TABLE I ALKYLENE-BIS-(N-METHYL-2,B-DIALKYLANILINES) R R I (3H3 l 3 R Y B.P., 0. mm Formula Method Press oH=- cm 148-152 0; 2 020mm A .CHa- (CH2)s- 158-163 0. 05 C21Ha0N2 B CHa (CH 150154 0.06 CzzHazNz A CH3- -(CH2)s 156464 0. O3 CzaHuNz B CHa- -(CH:)o- 184 0. 04 C24HaaN2 B GH3- CHaC C--CHz 158-162 0. 08 CzzHzsNz A 0,115- (CH;),-- 1 168173 0. 12 CMHBUN: B CzHr- -(CH 166-176 0.18 C25H3BN2 B C2H5- -(OH;) 174-184 0. 15 CWHZZN? B Various modifications mey be made in the method '20 4. The compound and compounds of the present invention without dep arting from the spirit or scopethereof, and it is to be under- CH3 CH3 stood that we limit ourselves only as defined in the apv pended claims. (CH')' N Havingdescribed our invention, what we claimas new 2 and desire to secure by Letters Patent is:

1. A compound having the formula The compound CH; CH3

CH3 CH3 ,QH; N-YN .3 I

N(CH:)r-N a Ha wherein Y is a straight chain polymethylene group cong g fij g f atoms References Cited iii the file of this patent CH! C CH UNITED STATES PATENTS 3 1 3: E 1 1,965,463 Jones July 3, 1934 QL CH N 2, 30,048 Biel Apr. 8. 1958 OTHER REFERENCES CH; 0H, m 7 Th d Braun et al.: Ber. der Deut. Chem. .GeselL, vol 51 e (1918),.p age 279.

C CH CH CH; Beilstein: Handb uchder Org. Chem, vol. 12 (1929),

| I pp. 825- 828, System No. 1679. N-( 0Ha)|N Dodds: Proceedings Royal Soc. (London) (1945),

e Series B, vol. 132, pp. 119-32 (pp. 119-23 relied on). ,H'

Boon: J. Chem. Soc. (1947), pp. 309, 310. 

1. A COMPOUND HAVING THE FORMULA 